Determination of the Mechanisms Regulating Mental Health Disorders in Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease (COPD) encompasses a range of chronic respiratory conditions characterised by progressive and irreversible obstruction of the airways. COPD represents a significant global health challenge, associated with high morbidity and mortality rates. It affects approximately 12% of the global population and is the 3rd leading cause of death worldwide, resulting in about 3 million deaths annually. A significant contributor to the COPD disease burden is the chronic inhalation of cigarette smoke (CS) particularly in industrialised countries. Given the irreversible nature of COPD, research predominantly concentrates on strategies to prevent or manage symptoms associated with the disease, with much of the burden comprising of the secondary extra-pulmonary comorbid conditions. These systemic comorbidities are believed to result from the "spill-over" of inflammatory mediators from the lungs into the bloodstream, thereby impacting other organs such as the brain. Among various comorbidities of COPD, anxiety disorders including generalised anxiety disorder (GAD) and panic disorder (PD) are prevalent in 35% to 68% of people with COPD, compared to just 4% in the general population. This heightened prevalence of anxiety is associated with increased mortality risk and a reduced quality of life for those with COPD. Furthermore, anxiety has been linked to a worsened disease prognosis, higher rates of acute exacerbations, increased hospitalisations, and non-compliance with treatment. Despite its significant impact and high prevalence, anxiety disorders in COPD often remain undiagnosed and untreated. This is largely attributed to a limited understanding of the mechanisms underlying mental health impairments in COPD. Consequently, there is a pressing need to address these gaps in knowledge to improve the diagnosis and management of anxiety disorders in this population. This Thesis investigates whether the "spill-over" of pulmonary inflammation into the systemic circulation can initiate neuroinflammation within the central nervous system and induce anxiety-like behaviours following CS exposure in a preclinical model of COPD. We next sought to determine the therapeutic potential of interventions aimed at targeting oxidative stress to alleviate anxiety-like behaviours associated with CS exposure. We first demonstrated that following 8 weeks of CS exposure, excessive lung inflammation was associated with systemic inflammation and anxiety-like behaviours, accompanied by increased microglial activation in brain regions implicated in anxiety circuits, such as the amygdala and hippocampus of male mice. Subsequently, we investigated whether inhibiting inflammation and oxidative stress with the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) inhibitor, apocynin, could prevent these behavioural abnormalities. Our results showed that apocynin treatment reduced lung and systemic inflammation, exhibited an anxiolytic effect and preserved microglial morphology in the amygdala and hippocampus. These neuroprotective effects of apocynin were likely mediated through alterations in the mitogen-activated protein kinase (MAPK) signalling pathway in the microglia. Beyond its established benefits in exercise capacity and overall quality of life, pulmonary rehabilitation shows promise in alleviating anxiety symptoms associated with COPD. In Chapter 4, we explored the therapeutic potential of combining aerobic exercise with an antioxidant treatment in CS-exposed male mice. As apocynin is not an FDA-approved treatment for medical use in individuals with COPD, we chose to use a natural antioxidant supplement, carnosine for the purpose of this study. Carnosine alone partially mitigated lung inflammation and anxiety-like behaviours, whereas the combination therapy showed broader benefits including attenuated weight loss, improved systemic inflammation, and restoration of social recognition memory impairments, potentially by mitigating neuroinflammation and oxidative stress in the amygdala. However, anxiety-like behaviours were not significantly improved by combination treatment potentially due to a transient stress response induced by involuntary exercise. In Chapter 5, we explored gender differences in COPD by investigating the effects of 8 weeks of CS exposure and a prophylactic combined intervention of carnosine supplementation and aerobic exercise in female mice. Female mice exhibited hallmark features of COPD, including weight loss, lung inflammation, and systemic oxidative stress. However, CS exposure was not associated with anxiety-like behaviours and social recognition memory impairments. While aerobic exercise alone partially improved lung inflammation, it also induced anxiety-like behaviours and social recognition memory deficits, associated with increased pro- inflammatory cytokines gene expression in the amygdala. The combination therapy alleviated these adverse effects, suggesting that when combined with aerobic exercise, carnosine supplementation can mitigate exercise-induced stress responses and neuroinflammation. These findings suggested that the synergistic effects of carnosine and aerobic exercise could offer a comprehensive therapeutic strategy for COPD management, particularly for female patients with comorbid anxiety disorders. In conclusion, our data suggests that 8 weeks of CS exposure is associated with anxiety-like behaviours and social recognition memory impairments in male mice. Targeting oxidative stress holds promise as a therapeutic strategy for alleviating anxiety disorders in individuals with COPD.<p></p>